This proposal will examine interactions involving intrarenal adenosine, sodium, potassium, the renin-angiotensin-aldosterone system and the sympathetic nervous system by studying the role of the renal nerves in renovascular hypertension. Denervation of the clipped kidney of the one-kidney one-clip and the two-kidney one-clip rat with established hypertension results in a decrease in arterial pressure that is not explained by changes in renin or sodium excretion. This depressor effect of renal denervation is associated with decreased sympathetic nervous system activity. These findings led to the hypothesis that in response to clipping, the afferent renal nerves activate the sympathetic nervous system in the Goldblatt models of hypertension. To determine whether adenosine might be a stimulus to afferent renal nerve discharge, adenosine has been infused into the renal artery or renal pelvis of the rat and dog and hypertension associated with increased sympathoadrenal activity has been produced when the renal nerves are intact. This suggests that there are adenosine sensitive nerve endings within or near the renal pelvis which modulate sympathetic nervous system activity. Recently, urinary adenosine concentration has been found to be three-fold greater in one-kidney one-clip hypertensive rats than in normotensive one-kidney controls. (1) To test the hypothesis that increased endogenous urinary adenosine enhances sympathetic activity via the afferent renal nerves in renovascular hypertension, urinary adenosine concentration will be lowered by infusing low dose adenosine deaminase (1 unit/kg/min) into the renal artery of one-kidney one-clip animals and arterial pressure and sympathetic activity will be measured. (2) To determine whether increased endogenous interstitial intrarenal adenosine inhibits renin release or (3) contributes to the maintenance of renal blood flow in one-kidney one-clip hypertension, interstitial adenosine concentration will be lowered by infusing high dose adenosine deaminase (10 units/kg/min) into the renal artery and renin-angiotensin activity and changes in renal blood flow will be measured. Pilot studies reveal that intrarenal mineralocorticoid administration attenuates the hypertensive response to renal artery adenosine infusion. (4) To determine whether increased potassium and/or hydrogen ion excretion are involved in the mechanism by which mineralocorticoid treatment blunts the intrarenal adenosine hypertensive response, renal afferent nerve response to adenosine will be measured before and after increasing renal pelvic potassium and/or hydrogen ion concentrations.